The objective of this proposal is to learn the etiology and the pathogenesis of Alzheimer disease and senile dementia of the Alzheimer type by characterizing its prominent lesion, the paired helical filaments (PHF) of the neurofibrillary tangles to learn its origin, and by studying the effects of this lesion on the function of the affected neurons. We have isolated a presumptive PHF protein (PHFP) subunit, a 50,000 daltons polypeptide from Alzheimer brains, and have observed at light microscopic level the staining of the neurofibrillary tangles with antiserum to this polypeptide raised in a rabbit. We will study the cytological localization of the PHFP to PHF at EM level with immunoperoxidase labeling technique. Attempts will be made to isolate the aluminum-induced neurofilaments from rabbits with experimental aluminum encephalopathy, and compare them chemically and immunologically with the PHF, the normal neurofilaments and the neurotubules. Synthesis and turnover of neuronal proteins in general and neurofilament and neurotubule proteins in particular will also be studied in rabbits with induced aluminum encephalopathy. We will characterize the neurofilament high molecular weight proteins in comparison with the neurofilament major protein, and the neurotubule associated proteins with respect to amino acid analysis, peptide maps and antigenic determinants. The methods of procedure outlined in this proposal include histochemical and immunological methodology, light and electron microscopic studies. Alzheimer dementia affects more than two million people in the U.S. and probably leads to more than 100,000 deaths per year. The information obtained from experiments outlined in this proposal will be of significance in regard to the design of further experiments leading towards an understanding of the disease mechanism.